Derivatives of 1-(o-bromophenoxy)-2-hydroxy-3-aminopropane



United States Patent S 78, Claims. (Cl. 260570.7)

It is known that certain aryloxypropanol'amines have antipyretic,vanalgetic and local anesthetic activity [(V. Petrow et al., J Pharm'acyPharmacol. 8,666 (1956), Y. M. Beasley et 211., P. Pharmacy Pharmacol,10, 46 (1958) We have now found that specific compounds not previouslyreported have useful sedative properties.

These compounds have the following formula:

in which R and R are hydrogen, lower alkyl of 1 to 8 carbon atoms,hydroxy lower alkyl of from 2 to 8 carbon atoms, cycloalkyl, aryl,aralkyl or, when taken together with the nitrogen atoms, pyrrolidino,morpholino or tetrahydroisoquinolyl.

Preferred are the secondary amines in which R is hydrogen and R is loweralkyl of 1 to 8 carbon atoms.

Especially preferred is the compound in which R is hydrogen and R istert. butyl.

The bases have utility as such in the form of their nontoxic aslts withpharmaceutically acceptable acids such as hydrochloric, sulfuric,maleic, ethaned'isulfonic etc. acids.

The compounds of this invention have been found to have a pure sedativeactivity rather than a biphased activity such as other sedatives havei.e., the barbiturates. This activity is realized when the compounds arecombined in unit dosage form with a common pharmaceutical carrier suchas lactose or magnesium sulfate. Such unit doses are then administeredinternally preferably orally several times daily to induce sedation.

It should be noted that 1-(0-br0m0phen0xy)-2-hydroxy-3-tert.butylaminopropane has an ED in a common pharmacological test forsedatives, namely antagonizing the stimulating effects ofmethamphetamine, which shows it to be about 7 times as active as itsn-butyl congener, 21 times as active as its isobutyl congener and over100 times as active as mepro'bam-ate.

The compounds of this invention are prepared by common synthetic schemesknown per se to the art such as reacting an o-bromophenylglycidic etheror an o-bromophenoxy-2-hydroxy-3-halopropane with an amine,alternatively o bromophenol can be reacted with an aminopropylene oxideor an amino-3-ha1o-2-propanol. These and other methods of preparationare illustrated by the following examples.

Example 1 A mixture of 18.9 g. of o-bromophenylglycidic ether (the2,3-oxi-dopropyl ether as prepared in British Pat. No. 622,297) and 5.0g. of isopropylamine in 50 m1. of ethanol is heated at reflux for 6hours. The solvent is removed. The residue is washed with water andextracted with benzene. The dried benzene extracts are saturated withdry hydrogen chloride to give 1-(o-bromophenoxy)-2-hydroxy-3-isopropylaminopropane hydrochloride, MJP. 124126 C.

Example 2 A mixture of 17.5 g. of o-bromophenylglycidic ether and 5 :3g. of pyrrolidine in ml. of ethanol is heated at reflux for 8 hours. Thesolvent is removed. The residue crystallizes upon standing to givel-(o-bromophenoxy-Z- hydroxy-3-pyrrolidinopropane, M.P. 7679 C.

Example 3 A mixture of l-(o-bromophenoxy)-2-hydroxy-3-tert.butylaminopropane (prepared as in Example 1) and 5.2 g. of ethyl iodidein 20 ml. of ethanol is heated under reflux for 2 hours. The alcohol istaken oil in vacuo to leave an oily residue which is washed with waterthen separated. The oil is dissolved in dilute sulfuric acid, treatedwith sodium nitrite and extracted with ether. The tertiary baseseparates after treatment with alkali and is taken up in ether. Thehydrochloride salt of the N-ethyl- N-tert. butyl congener is formed withdry hydrogen chloride gas, M.P. 144-146" C.

Example 4 Using the stock reactions above and molar equivalent amountsof similar reactants the following compounds are prepared.

N\ Form M.P. O.

NH-C3H1 HC1 131-134 NH-CAT-lo H 01.. 92-95 NHisoO4H0 HO 130-13 -NHtert.-C1H0 Base. B P. 142-145 1 mm. HCl. 150-151 Maleate 112-114 Sulfate188-191 Phosphate. 112-114 -NHCsH17 01.- 133-136 -NH sec 00H" H01104-106 03H; NH(i lCaH7 HC1 158-160 NHCH;CH=CH: HC1 -128 CHiOH NHCCH1CH3Hc1 122-124 CH OH NH Hc1- 192-194 NH- HCl---- 142-144 -NH-orn- H01140-143 N(CHa)2 Base B.P. 134-139 1 mm. 1101 110-112 N(C2H5)v HCL-124-126 -N(isoCaH1)1 H01- 172-174 N(C4H9)z HCl 95-98 N 0 Base- 83-85HC1. -133 3 4. What is claimed is: References Cited by the Examiner 1. ACOmPOlIIld Of the formula: 1)

Br 2,967,201 1/61 Soper 260570.7 Q 3,033,640 5/62 Hofer et a1. 260570.7CH;-CH-CHzNH-R 3,083,139 3/63 Aspergren et a1. 167--65 1 3,089,826 5/63Sahyun et a1. 167-65 3,105,854 63 Druey et a1. 260570.7 in which R islower alkyl of from 1 to 8 carbon atoms. FOREIGN PATENTS 2. A'compoundof the formula: 10

213,872 3/61 Austria.

' OTHER REFERENCES @o-cm-cn-cnmmmm 04H, David et a1.: Jour. Pharm. andPharmacoL, v01. 10,

V H pp. 60-70 (1958).

- Goodsell at al.: I our. Pharmacol. and Exptl. Therap., 3.1-(o-bromophenoxy)-2-hydroxy-3-tert. butylamino- VOL 110, PP- 251-9propane h d h1 id Beasley at 211.: J. Pharmacy and Pharmacology, v01.

4. l-(o-bromophenoxy) 2 hydroxy-3-benzy1amino- 1 PP- 47-59, 1953- ro aneh drochloride. p 5? 1 (Z-bromophenoxy)-2-hydroxy-3-hydroxyloweral-CHARLES PARKER Pnmmy Exammer' kylaminopropane. NICHOLAS S. RIZZO,Examiner.

1. A COMPOUND OF THE FORMULA: